681 results on '"R. Giugliani"'
Search Results
2. Evaluation of impact of anti-idursulfase antibodies during long-term idursulfase enzyme replacement therapy in mucopolysaccharidosis II patients
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R. Giugliani, P. Harmatz, S.A. Jones, N.J. Mendelsohn, A. Vellodi, Y. Qiu, C.J. Hendriksz, S. Vijayaraghavan, D.A.H. Whiteman, and A. Pano
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Neutralizing antibodies ,Idursulfase ,Hunter syndrome ,Enzyme replacement therapy ,Cognitive impairment ,Immunogenicity ,Glycosaminoglycans ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Objectives: This 109-week, nonrandomized, observational study of mucopolysaccharidosis II (MPS II) patients already enrolled in the Hunter Outcome Survey (HOS) (NCT00882921), assessed the long-term immunogenicity of idursulfase, and examined the effect of idursulfase-specific antibody generation on treatment safety (via infusion-related adverse events [IRAEs]) and pharmacodynamics (via urinary glycosaminoglycans [uGAGs]). Methods: Male patients ≥5 years, enrolled in HOS regardless of idursulfase treatment status were eligible. Blood/urine samples for anti-idursulfase antibody testing and uGAG measurement were collected every 12 weeks. Results: Due to difficulties in enrolling treatment-naïve patients, data collection was limited to 26 enrolled patients of 100 planned patients (aged 5.1–35.5 years) all of whom were non-naïve to treatment. Fifteen (58%) patients completed the study. There were 11/26 (42%) seropositive patients at baseline (Ab+), and 2/26 (8%) others developed intermittent seropositivity by Week 13. A total of 9/26 patients (35%) had ≥1 sample positive for neutralizing antibodies. Baseline uGAG levels were low due to prior idursulfase treatment and did not change appreciably thereafter. Ab+ patients had persistently higher uGAG levels at entry and throughout the study than Ab− patients. Nine of 26 (34%) patients reported IRAEs. Ab+ patients appeared to have a higher risk of developing IRAEs than Ab− patients. However, the relative risk was not statistically significant and decreased after adjustment for age. Conclusions: 50% of study patients developed idursulfase antibodies. Notably Ab+ patients had persistently higher average uGAG levels. A clear association between IRAEs and antibodies was not established.
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- 2017
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3. Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa
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D. Hughes, R. Giugliani, N. Guffon, S. A. Jones, K. E. Mengel, R. Parini, R. Matousek, S. M. Hawley, and A. Quartel
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Morquio syndrome A ,Adults ,Adulthood ,Advanced disease ,Long-term ,Enzyme replacement therapy ,Medicine - Abstract
Abstract Background This post hoc subanalysis examined outcomes in adult patients with Morquio A (mucopolysaccharidosis IVA) who received enzyme replacement therapy (ERT) with elosulfase alfa over a 120-weeks period. Patients ≥18 years of age evaluated in an open-label, long-term extension study of elosulfase alfa (modified per protocol [MPP], n = 32; intent-to-treat [ITT], n = 37; MOR-005; NCT01415427) were compared with the ≥18-year-old untreated population with 2-years follow-up from a Morquio A natural history study (n = 10; MorCAP; NCT00787995). The MOR-005 MPP population excluded patients who underwent orthopedic surgical procedures or were noncompliant with study protocol (defined as missing ≥20% of ERT infusions). No MorCAP patients underwent orthopedic surgical procedures during the relevant time period. Endurance was assessed by the 6-min walk test (6MWT) and 3-min stair climb test (3MSCT). Activities of daily living (ADLs) were assessed by the MPS Health Assessment Questionnaire (MPS HAQ). Results Least squares (LS) mean (SE) 6MWT distances increased by 34.9 (11.7) m (MPP) and 30.5 (10.8) m (ITT) by week 120; LS mean (SE) change in 3MSCT at week 120 was 6.7 (1.8) stairs/min (MPP) and 5.9 (1.7) stairs/min (ITT). MorCAP patients showed no improvement in 6MWT distance or 3MSCT over a similar period of time. Pulmonary function measures remained unchanged in both MOR-005 and MorCAP adults. All MPS HAQ domain scores improved in MOR-005 adults, whereas MorCAP adults had unchanged caregiver assistance and mobility outcomes and worsened self-care outcomes. Conclusions Long-term ERT in adult patients with Morquio A was associated with increased endurance and improvement in performance of ADLs. Trial registration Trial Registration NCT01415427 . Name of registry: Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome). Registered 8 August 2011, retrospectively registered.
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- 2017
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4. Prevalence of ERα-397 PvuII C/T, ERα-351 XbaI A/G and PGR PROGINS polymorphisms in Brazilian breast cancer-unaffected women
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J. Giacomazzi, E. Aguiar, E.I. Palmero, A.V. Schmidt, G. Skonieski, D.D. Filho, H. Bock, M.L. Saraiva-Pereira, I.P. Ewald, L. Schuler-Faccini, S.A. Camey, M. Caleffi, R. Giugliani, and P. Ashton-Prolla
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Genetic polymorphisms ,Estrogen receptor gene ,Progesterone receptor gene ,Breast cancer susceptibility ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Polymorphisms of hormone receptor genes have been linked to modifications in reproductive factors and to an increased risk of breast cancer (BC). In the present study, we have determined the allelic and genotypic frequencies of the ERα-397 PvuII C/T, ERα-351 XbaI A/G and PGR PROGINS polymorphisms and investigated their relationship with mammographic density, body mass index (BMI) and other risk factors for BC. A consecutive and unselected sample of 750 Brazilian BC-unaffected women enrolled in a mammography screening program was recruited. The distribution of PGR PROGINS genotypic frequencies was 72.5, 25.5 and 2.0% for A1A1, A1A2 and A2A2, respectively, which was equivalent to that encountered in other studies with healthy women. The distribution of ERα genotypes was: ERα-397 PvuII C/T: 32.3% TT, 47.5% TC, and 20.2% CC; ERα-351 XbaI A/G: 46.3% AA, 41.7% AG and 12.0% GG. ERα haplotypes were 53.5% PX, 14.3% Px, 0.3% pX, and 32.0% px. These were significantly different from most previously published reports worldwide (P < 0.05). Overall, the PGR PROGINS genotypes A2A2 and A1A2 were associated with fatty and moderately fatty breast tissue. The same genotypes were also associated with a high BMI in postmenopausal women. In addition, the ERα-351 XbaI GG genotype was associated with menarche ≥12 years (P = 0.02). ERα and PGR polymorphisms have a phenotypic effect and may play an important role in BC risk determination. Finally, if confirmed in BC patients, these associations could have important implications for mammographic screening and strategies and may be helpful to identify women at higher risk for the disease.
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- 2012
5. Severity score system for progressive myelopathy: development and validation of a new clinical scale
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R.M. Castilhos, D. Blank, C.B.O. Netto, C.F.M. Souza, L.N.T. Fernandes, I.V.D. Schwartz, R. Giugliani, and L.B. Jardim
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Japanese Orthopaedic Association ,Severity Score System for Progressive Myelopathy ,Mucopolysaccharidosis ,Mucolipidosis ,Adrenomyeloneuropathy ,Progressive myelopathies ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Progressive myelopathies can be secondary to inborn errors of metabolism (IEM) such as mucopolysaccharidosis, mucolipidosis, and adrenomyeloneuropathy. The available scale, Japanese Orthopaedic Association (JOA) score, was validated only for degenerative vertebral diseases. Our objective is to propose and validate a new scale addressing progressive myelopathies and to present validating data for JOA in these diseases. A new scale, Severity Score System for Progressive Myelopathy (SSPROM), covering motor disability, sphincter dysfunction, spasticity, and sensory losses. Inter- and intra-rater reliabilities were measured. External validation was tested by applying JOA, the Expanded Disability Status Scale (EDSS), the Barthel index, and the Osame Motor Disability Score. Thirty-eight patients, 17 with adrenomyeloneuropathy, 3 with mucopolysaccharidosis I, 3 with mucopolysaccharidosis IV, 2 with mucopolysaccharidosis VI, 2 with mucolipidosis, and 11 with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy participated in the study. The mean ± SD SSPROM and JOA scores were 74.6 ± 11.4 and 12.4 ± 2.3, respectively. Construct validity for SSPROM (JOA: r = 0.84, P < 0.0001; EDSS: r = -0.83, P < 0.0001; Barthel: r = 0.56, P < 0.002; Osame: r = -0.94, P < 0.0001) and reliability (intra-rater: r = 0.83, P < 0.0001; inter-rater: r = 0.94, P < 0.0001) were demonstrated. The metric properties of JOA were similar to those found in SSPROM. Several clinimetric requirements were met for both SSPROM and JOA scales. Since SSPROM has a wider range, it should be useful for follow-up studies on IEM myelopathies.
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- 2012
6. Study of the comprehension of the scientific method by members of a university health research laboratory
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A.C. Burlamaque-Neto, G.R. Santos, L.M. Lisbôa, J.R. Goldim, C.L.B. Machado, U. Matte, and R. Giugliani
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Scientific method ,Complexity ,Academic scientific research ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
In Brazil, scientific research is carried out mainly at universities, where professors coordinate research projects with the active participation of undergraduate and graduate students. However, there is no formal program for the teaching/learning of the scientific method. The objective of the present study was to evaluate the comprehension of the scientific method by students of health sciences who participate in scientific projects in an academic research laboratory. An observational descriptive cross-sectional study was conducted using Edgar Morin complexity as theoretical reference. In a semi-structured interview, students were asked to solve an abstract logical puzzle - TanGram. The collected data were analyzed using the hermeneutic-dialectic analysis method proposed by Minayo and discussed in terms of the theoretical reference of complexity. The students’ concept of the scientific method is limited to participation in projects, stressing the execution of practical procedures as opposed to scientific thinking. The solving of the TanGram puzzle revealed that the students had difficulties in understanding questions and activities focused on subjects and their processes. Objective answers, even when dealing with personal issues, were also reflected on the students’ opinions about the characteristics of a successful researcher. Students’ difficulties concerning these issues may affect their scientific performance and result in poorly designed experiments. This is a preliminary study that should be extended to other centers of scientific research.
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- 2012
7. Prevalence of the STK15 F31I polymorphism and its relationship with mammographic density
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J. Giacomazzi, E. Aguiar, E.I. Palmero, A.V. Schmidt, G. Skonieski, D. Duarte Filho, H. Bock, M.L. Saraiva-Pereira, L. Schuler-Faccini, S.A. Camey, M. Caleffi, R. Giugliani, and P. Ashton-Prolla
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STK15 F31I polymorphism ,Breast cancer risk ,Mammographic density ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Several studies have identified the single nucleotide polymorphism STK15 F31I as a low-penetrance risk allele for breast cancer, but its prevalence and risk association in the Brazilian population have not been determined. The goal of this study was to identify the frequency of this polymorphism in the Brazilian setting. Considering the high degree of admixture of our population, it is of fundamental importance to validate the results already reported in the literature and also to verify the relationship between this variant and breast cancer risk. A total of 750 women without breast cancer were genotyped using the TaqMan PCR assay for STK15 F31I polymorphism. Clinical information was obtained from review of the medical records and mammographic density from the images obtained using the BI-RADS System. The estimated risk of developing cancer was calculated according to the Gail model. The genotypic frequencies observed in this study were 4.5, 38.7, and 56.6%, respectively, for the STK15 F31I AA, AT and TT genotypes. The AT and AA genotypes were encountered significantly more often in premenopausal women with moderately dense, dense and heterogeneously dense breast tissue (P = 0.023). In addition, the presence of the TT genotype was significantly associated with age at menarche ≥12 years (P = 0.023). High mammographic density, associated with increased breast cancer risk, was encountered more frequently in premenopausal women with the risk genotypes STK15 F31I AA and AT. The genotypic frequencies observed in our Brazilian sample were similar to those described in other predominantly European populations.
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- 2011
8. The effect of Mycoplasma and mycoplasma removal agent on the hydrolase activity in fibroblasts of patients with lysosomal diseases Efecto de Mycoplasma y del agente de eliminación de micoplasmas en la actividad de las hidrolasas en fibroblastos de pacientes con enfermedades lisosomales
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F. T. S. Souza, L. S. Sostruznik, R. C. Scolari, K. J. M. Castro, C. V. Andrade, R. Giugliani, and J. C. Coelho
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Mycoplasma ,Cultivo de fibroblastos ,Hidrolasas lisosomales ,Enfermedades lisosomales ,Fibroblast culture ,Lysosomal hydrolases ,Lysosomal diseases ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
This study was designed to evaluate the effect of mycoplasma contamination on acid hydrolase activity and the action of the mycoplasma removal agent (MRA), in cultures of human fibroblasts from individuals with lysosomal diseases. For this purpose, we measured the activity of the b-galactosidase, arylsulphatase B (ASB), hexosaminidase A and a-glucosidase enzymes. The activity of the above mentioned enzymes in fibroblasts contaminated by mycoplasma was measured before and after the addition of the MRA. The results were then compared to the enzymatic activity in contamination-free cultures. Only the ASB enzyme showed significant alteration in activity both in the presence of mycoplasma and MRA. The remaining enzymes did not suffer significant interference by the presence of the two agents. Of the four enzymes tested, three did not suffer significant alterations by the presence of the mycoplasma nor from the MRA. However, the activity measured in the ASB enzyme increased significantly in the presence of mycoplasma and MRA and could lead to a doubtful diagnosis. Therefore, we suggest that contamination should be prevented by using aseptic techniques as well as the MRA in those fibroblast cultures that cannot be discarded.Este estudio fue diseñado para evaluar el efecto de la contaminación por micoplasmas sobre la actividad de hidrolasas ácidas y la acción del agente de eliminación de micoplasmas (MRA) en cultivos de fibroblastos humanos de pacientes con enfermedades lisosomales. Se midió la actividad de la b-galactosidasa, arilsulfatasa B (ASB), hexosaminidasa A y a-glucosidasa en estos cultivos. La actividad de estas enzimas en los fibroblastos contaminados por micoplasmas se midió antes y después de la adición de MRA. Los resultados se compararon con los obtenidos en cultivos libres de contaminación. Sólo la enzima ASB demostró alteración significativa en la actividad, tanto en presencia de micoplasmas como con la adición de MRA. Las enzimas restantes no sufrieron alteraciones significativas en presencia de micoplasmas, ni tras la adición de MRA. La actividad medida para la enzima ASB aumentó significativamente en presencia de micoplasmas y MRA, lo que podría conducir a un diagnóstico dudoso. Por lo tanto, sugerimos evitar la contaminación con micoplasmas mediante el uso de técnicas asépticas y la utilización de MRA en los cultivos de fibroblastos que no se puedan descartar.
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- 2010
9. Genetics of homocysteine metabolism and associated disorders
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S. Brustolin, R. Giugliani, and T.M. Félix
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Homocysteine ,Hyperhomocysteinemia ,Folate metabolism ,Single nucleotide polymorphism ,Susceptibility genes ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.
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- 2010
10. The polymorphism of the serotonin-2A receptor T102C is associated with age
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P.F.C. Jobim, P.A.S. Prado-Lima, C.H.A. Schwanke, R. Giugliani, and I.B.M. Cruz
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Mean life span ,Serotonin ,Receptor 2A ,T102C polymorphism ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Epidemiological investigations suggest that T102C polymorphism of gene 5-HT2A may be associated with mean life span because diseases and behaviors related to this polymorphism, such as schizophrenia, suicide, aggression, and addiction, may potentially shorten mean life span. A sample of 687 individuals without previous neuropsychiatric disease was genotyped and separated into 3 groups according to their gender and age: 14-45 years old, 46-64 years old and 65-100 years old. Molecular genotyping was performed using the technique of polymerase chain reaction followed by restriction fragment length polymorphism using HpaII restriction enzyme. 5-HT2A genotype frequencies were: TT = 21.5% (148), CC = 16.6% (114) and TC = 61.9% (425) and allele frequencies were T = 52.5% and C = 46.5%. Significant differences were found between mean age of the TT genotype carriers (60.27 ± 12.60 years) and TC genotype carriers (56.80 ± 13.18 years) of T102C polymorphism of gene 5-HT2A (P = 0.026) as well as the age groups (P = 0.012). Carriers of genotype TT were older than the other two genotypes, whereas carriers of genotype CC had an intermediate age compared with TT and CC subjects. The present results demonstrate an association between T102C polymorphism of gene 5-HT2A and age. Our results suggest that T102C polymorphism of gene 5-HT2A is associated with mean life span, and thus this gene becomes a possible candidate for the group of adaptive genes to meat consumption proposed in the literature. Further studies should be conducted in order to elucidate this association.
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- 2008
11. Transient high-level expression of ß-galactosidase after transfection of fibroblasts from GM1 gangliosidosis patients with plasmid DNA
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R.C. Balestrin, G. Baldo, M.B. Vieira, R. Sano, J.C. Coelho, R. Giugliani, and U. Matte
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GM1 gangliosidosis ,ß-galactosidase deficiency ,Gene therapy ,Lysosomal storage disorder ,Lipofectamine ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
GM1 gangliosidosis is an autosomal recessive disorder caused by the deficiency of lysosomal acid hydrolase ß-galactosidase (ß-Gal). It is one of the most frequent lysosomal storage disorders in Brazil, with an estimated frequency of 1:17,000. The enzyme is secreted and can be captured by deficient cells and targeted to the lysosomes. There is no effective treatment for GM1 gangliosidosis. To determine the efficiency of an expression vector for correcting the genetic defect of GM1 gangliosidosis, we tested transfer of the ß-Gal gene (Glb1) to fibroblasts in culture using liposomes. ß-Gal cDNA was cloned into the expression vectors pSCTOP and pREP9. Transfection was performed using 4 µL lipofectamine 2000 and 1.5-2.0 µg DNA. Cells (2 x 10(5)/well) were harvested 24 h, 48 h, and 7 days after transfection. Enzyme specific activity was measured in cell lysate and supernatant by fluorometric assay. Twenty-four hours after transfection, treated cells showed a higher enzyme specific activity (pREP9-ß-Gal: 621.5 ± 323.0, pSCTOP-ß-Gal: 714.5 ± 349.5, pREP9-ß-Gal + pSCTOP-ß-Gal: 1859.0 ± 182.4, and pREP9-ß-Gal + pTRACER: 979.5 ± 254.9 nmol·h-1·mg-1 protein) compared to untreated cells (18.0 ± 3.1 for cell and 32.2 ± 22.2 nmol·h-1·mg-1 protein for supernatant). However, cells maintained in culture for 7 days showed values similar to those of untreated patients. In the present study, we were able to transfect primary patients' skin fibroblasts in culture using a non-viral vector which overexpresses the ß-Gal gene for 24 h. This is the first attempt to correct fibroblasts from patients with GM1 gangliosidosis by gene therapy using a non-viral vector.
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- 2008
12. Genomic analysis of Brazilian patients with Fabry disease
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F.S. Pereira, L.B. Jardim, C.B. Netto, M.G. Burin, C. Cecchin, R. Giugliani, and U.S. Matte
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Fabry disease ,Lysosomal disorders ,a-Galactosidase A ,Globotriaosylceramide storage ,GLA gene ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Fabry disease is an X-linked lysosomal disorder due to a-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the a-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the a-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease, the finding of the same mutation previously detected in another Fabry family from our region raises the possibility of some founder effect, or genetic drift. Finally, the present study highlights the importance of molecular analysis for carrier detection and genetic counseling.
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- 2007
13. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations
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E. C. Neto, J. Schulte, R. Rubim, E. Lewis, J. DeMari, C. Castilhos, A. Brites, R. Giugliani, K.P. Jensen, and B. Wolf
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Newborn screening ,Biotinidase deficiency ,Biotinidase ,Mutations ,Enzyme assay ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Biotinidase deficiency is an inherited metabolic disorder characterized by neurological and cutaneous symptoms. Fortunately, it can be treated and the symptoms prevented by oral administration of the vitamin biotin. Using dried blood-soaked filter paper cards, biotinidase activity was determined in the sera of 225,136 newborns in Brazil. Mutation analysis performed on DNA from 21 babies with low serum biotinidase activity confirmed that 3 had profound biotinidase deficiency (less than 10% of mean normal sera biotinidase activity), 10 had partial biotinidase deficiency (10 to 30% of mean normal serum activity), 1 was homozygous for partial biotinidase deficiency, 4 were heterozygous for either profound or partial deficiency, and 3 were normal. Variability in serum enzyme activities and discrepancies with mutation analyses were probably due to inappropriate handling and storage of samples sent to the laboratory. Obtaining an appropriate control serum at the same time as that of the suspected child will undoubtedly decrease the false-positive rate (0.09%). Mutation analysis can be used to confirm the genotype of these children. The estimated incidence of biotinidase deficiency in Brazil is about 1 in 9,000, higher than in most other countries. Screening and treatment of biotinidase deficiency are effective and warranted. These results strongly suggest that biotinidase deficiency should be included in the newborn mass screening program of Brazil.
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- 2004
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14. Effect of collection, transport, processing and storage of blood specimens on the activity of lysosomal enzymes in plasma and leukocytes
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M. Burin, C. Dutra-Filho, J. Brum, T. Mauricio, M. Amorim, and R. Giugliani
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lysosomal storage diseases ,lysosomal enzymes ,inborn errors of metabolism ,reference laboratories ,storage of blood samples ,sample handling ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
This study was designed to evaluate the effect of different conditions of collection, transport and storage on the quality of blood samples from normal individuals in terms of the activity of the enzymes ß-glucuronidase, total hexosaminidase, hexosaminidase A, arylsulfatase A and ß-galactosidase. The enzyme activities were not affected by the different materials used for collection (plastic syringes or vacuum glass tubes). In the evaluation of different heparin concentrations (10% heparin, 5% heparin, and heparinized syringe) in the syringes, it was observed that higher doses resulted in an increase of at least 1-fold in the activities of ß-galactosidase, total hexosaminidase and hexosaminidase A in leukocytes, and ß-glucuronidase in plasma. When the effects of time and means of transportation were studied, samples that had been kept at room temperature showed higher deterioration with time (72 and 96 h) before processing, and in this case it was impossible to isolate leukocytes from most samples. Comparison of heparin and acid citrate-dextrose (ACD) as anticoagulants revealed that ß-glucuronidase and hexosaminidase activities in plasma reached levels near the lower normal limits when ACD was used. In conclusion, we observed that heparin should be used as the preferable anticoagulant when measuring these lysosomal enzyme activities, and we recommend that, when transport time is more than 24 h, samples should be shipped by air in a styrofoam box containing wet ice.
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- 2000
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15. Arylsulfatase A pseudodeficiency in healthy Brazilian individuals
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C.G. Pedron, P.A. Gaspar, R. Giugliani, and M.L.S. Pereira
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arylsulfatase A ,pseudodeficiency ,metachromatic leukodystrophy ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Molecular alterations associated with arylsulfatase A pseudodeficiency (ASA-PD) were characterized by PCR and restriction endonuclease analysis in a sample of healthy individuals from Brazil. ASA activity was also assayed in all subjects. Two individuals homozygous for the N350S and 1524+95A®G mutations were detected, corresponding to a frequency of 1.17% (4 of 324 alleles). The individual frequency of the N350S mutation was 20.7% (71 of 342 alleles) and 7.9% (27 of 342 alleles) for the 1524+95A®G mutation. The frequency of the ASA-PD allele in our population was estimated to be 7.9%. This is the first report of ASA-PD allele frequency in a South American population. In addition, the methods used are effective and suitable for application in countries with limited resources. All patients with low ASA activity should be screened for ASA-PD as part of the diagnostic procotol for metachromatic leukodystrophy.
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- 1999
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16. Effect of dimethylsulfoxide on sphingomyelinase activity and cholesterol metabolism in Niemann-Pick type C fibroblasts
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F.B. Scalco, R. Giugliani, P. Tobo, and J.C. Coelho
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cholesterol metabolism ,sphingomyelinase ,Niemann-Pick disease ,lysosomal storage disorders ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Niemann-Pick type C (NPC) fibroblasts present a large concentration of cholesterol in their cytoplasm due to a still unidentified deficiency in cholesterol metabolism. The influence of dimethylsulfoxide (DMSO) on the amount of intracellular cholesterol was measured in 8 cultures of normal fibroblasts and in 7 fibroblast cultures from NPC patients. DMSO was added to the fibroblast cultures at three different concentrations (1, 2 and 4%, v/v) and the cultures were incubated for 24 h. Sphingomyelinase activity was significantly increased in both groups of cells only when incubated with 2% DMSO (59.4 ± 9.1 and 77.0 ± 9.1 nmol h-1 mg protein-1, controls without and with 2% DMSO, respectively; 47.7 ± 5.2 and 55.8 ± 4.1 nmol h-1 mg protein-1, NPC without and with 2% DMSO, respectively). However, none of the DMSO concentrations used altered the amount of cholesterol in the cytoplasm of NPC cells (0.704 ± 0.049, 0.659 ± 0.041, 0.688 ± 0.063 and 0.733 ± 0.088 mg/mg protein, without DMSO, 1% DMSO, 2% DMSO and 4% DMSO, respectively). This finding suggests that sphingomyelinase deficiency is a secondary defect in NPC and shows that DMSO failed to remove the stored cholesterol. These data do not support the use of DMSO in the treatment of NPC patients.
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- 1999
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17. BONE DISEASE IN MUCOPOLYSACCHARIDOSIS I: MORPHOLOGICAL AND BIOMECHANICAL PROPERTIES AND EFFECT OF GENE EDITING WITH CRISPR/CAS9 SYSTEM
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H. Santos, E. Gaviolli, V. Leitune, L.N. Pimental-Vera, R.S. Schuh, R. Giugliani, and G. Baldo
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Cancer Research ,Transplantation ,Oncology ,Immunology ,Immunology and Allergy ,Cell Biology ,Genetics (clinical) - Published
- 2022
18. Sustained Improvement of Interstitial Lung Disease Following Enzyme Replacement Therapy with Olipudase Alfa in Children and Adults with Chronic Acid Sphingomyelinase Deficiency
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K.I. Berger, M. Scarpa, G.A. Diaz, R. Giugliani, R. Lachmann, M.P. Wasserstein, F. Bonella, S.L.F. Walsh, W.A. Wuyts, A. Jessel, A.M. Rawlings, and M. Kumar
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Medizin - Published
- 2022
19. NEONATAL INTRAVENOUS INJECTION OF CRISPR/CAS9 LIPOSOMAL COMPLEX DOES NOT INCREASE TUMOR FREQUENCY IN MICE
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B.L.S. Pereira, E.P. Couto, E. Poletto, B.B.B.B. Medeiros-Neves, N.T. Brazil, H.F. Teixeira, U. Matte, R. Giugliani, R.S. Schuh, and G. Baldo
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Cancer Research ,Transplantation ,Oncology ,Immunology ,Immunology and Allergy ,Cell Biology ,Genetics (clinical) - Published
- 2022
20. Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus
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Alessandro P. Burlina, Mark Thomas, Alison Muir, Michael West, Aleš Linhart, Sandro Feriozzi, Joan Fletcher, Ana Jovanovic, James C. Moon, R. Giugliani, João Paulo Oliveira, Juan Politei, Raphael Schiffmann, Michael Mauer, Daniel G. Bichet, Olivier Lidove, Guillem Pintos-Morell, Christiane Auray-Blais, Alberto Ortiz, Patricio Aguiar, Duncan Cole, Mathias Beck, Perry M. Elliott, Camilla Tøndel, Derralynn Hughes, David Moreno-Martinez, Albina Nowak, Mirjam Langeveld, Andrew Talbot, Einar Svarstad, David G. Warnock, Christoph Kampmann, Paula Rozenfeld, Ulla Feldt-Rasmussen, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Free Hospital [London, UK], Endocrinology, Amsterdam Gastroenterology Endocrinology Metabolism, and ACS - Diabetes & metabolism
- Subjects
0301 basic medicine ,Male ,Delphi Technique ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Delphi method ,Disease ,030105 genetics & heredity ,Kidney ,Biochemistry ,0302 clinical medicine ,Endocrinology ,Clinical outcomes ,Clinical Trials as Topic ,Globosides ,Trihexosylceramides ,Middle Aged ,3. Good health ,Clinical trial ,Isoenzymes ,Treatment Outcome ,Inclusion and exclusion criteria ,Secondary Outcome Measure ,Female ,Adult ,medicine.medical_specialty ,Consensus ,Lysosomal storage disorders ,03 medical and health sciences ,Quality of life (healthcare) ,Inherited metabolic disorders ,Genetics ,medicine ,Humans ,Enzyme Replacement Therapy ,Intensive care medicine ,Molecular Biology ,Fabry disease ,Sphingolipids ,business.industry ,Clinical study design ,medicine.disease ,Delphi consensus ,alpha-Galactosidase ,Quality of Life ,Fabry Disease ,Glycolipids ,business ,030217 neurology & neurosurgery - Abstract
International audience; Background: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD.Methods and findings: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial.Conclusion: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.
- Published
- 2020
21. Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey
- Author
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A. Mehta, J.T.R. Clarke, R. Giugliani, P. Elliott, A. Linhart, M. Beck, and G. Sunder-Plassmann
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Fabry's disease -- Development and progression ,Fabry's disease -- Genetic aspects ,Fabry's disease -- Patient outcomes ,Fabry's disease -- Research ,Kidney diseases -- Patient outcomes ,Kidney diseases -- Research ,Health - Published
- 2009
22. Universal newborn screening: A roadmap for action
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N. Zhong, Edward R.B. McCabe, R. Giugliani, X. Zeng, M.D. Santos, Bradford L. Therrell, A. Umemoto, Xinliang Zhao, Ida Vanessa Doederlein Schwartz, Christopher P Howson, P. Huhtinen, C.S. Palubiak, B. Cedergren, J. Wang, and Carmencita Padilla
- Subjects
0301 basic medicine ,Civil society ,Economic growth ,Latin Americans ,Endocrinology, Diabetes and Metabolism ,030105 genetics & heredity ,Asia pacific region ,Global Health ,Biochemistry ,History, 21st Century ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Neonatal Screening ,030225 pediatrics ,Political science ,Genetics ,Humans ,Molecular Biology ,health care economics and organizations ,Newborn screening ,Government ,Genetic Diseases, Inborn ,Infant, Newborn ,food and beverages ,History, 20th Century ,Private sector ,Genetics, Population ,Action (philosophy) - Abstract
Newborn screening (NBS) prevents morbidity and mortality by screening babies for selected disorders in the first days of life so that early diagnosis and treatment can be initiated. Congenital disorders impact an estimated 8 million or 6% of annual births worldwide, and of the top five that contribute 25% to the global burden of these disorders, three can be identified and managed by NBS. There are determined pockets of activity in Latin America, Sub-Saharan Africa, and the Asia Pacific region, where partnerships among government, non-governmental organizations, academia, the private sector and civil society are developing novel NBS programs that are both saving lives and preventing disability in those who survive.
- Published
- 2018
23. Corrigendum to Universal newborn screening: A roadmap for action molecular genetics and metabolism 124 (2018) 177–183
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P. Huhtinen, C.S. Palubiak, N. Zhong, R. Giugliani, Edward R.B. McCabe, M.D. Santos, A. Umemoto, Christopher P Howson, Xinliang Zhao, B. Cedergren, Carmencita D. Padilla, Bradford L. Therrell, Ida Vanessa Doerderlein Schwartz, X. Zeng, and J. Wang
- Subjects
Newborn screening ,medicine.medical_specialty ,Endocrinology ,Action (philosophy) ,business.industry ,Endocrinology, Diabetes and Metabolism ,Molecular genetics ,Genetics ,Medicine ,Computational biology ,business ,Molecular Biology ,Biochemistry - Published
- 2019
24. p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients
- Author
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Ursula da Silveira Matte, Márcia Gonçalves Ribeiro, Aída Lemes, Andrea Schenone, G.G.G. da Fonseca, R. Giugliani, Gabriela Pasqualim, Marina Szlago, and M.V.M. Rojas
- Subjects
Pathology ,medicine.medical_specialty ,Heart disease ,business.industry ,Carpal tunnel surgery ,Enzyme replacement therapy ,medicine.disease ,Mucopolysaccharidosis type I ,Dysplasia ,Mucopolysaccharidosis I ,Genetics ,medicine ,Iduronidase ,Scheie syndrome ,business ,Genetics (clinical) - Abstract
Mucopolysaccharidosis type I is a rare autosomal recessive disorder caused by deficiency of α-l-iduronidase (IDUA) which leads to a wide spectrum of clinical severity. Here, we describe the case of four male patients who present the previously undescribed p.L18P mutation. Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, claw hands and underwent bilateral carpal tunnel surgery at 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented claw hands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptide to 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease, or cognitive impairment.
- Published
- 2014
25. A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy
- Author
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Nathalie Goemans, Eugenio Mercuri, Elena Belousova, Hirofumi Komaki, Alberto Dubrovsky, Craig M. McDonald, John E. Kraus, Afrodite Lourbakos, Zhengning Lin, Giles Campion, Susanne X. Wang, Craig Campbell, A. Araujo, E. Bertini, P. Born, C. Cances, B. Chabrol, J.-H. Chae, J. Colomer Oferil, G.P. Comi, J.-M. Cuisset, G. D'Anjou, I. Desguerre, R. Erazo Torricelli, R. Escobar, D. Feder, A. Ferlini, R. Giugliani, E. Henricson, A. Herczegfalvi, Y.-J. Jong, S. Kimura, J.-B. Kirschner, K. Kleinsteuber, A. Kostera-Pruszczyk, M. Kudr, W. Mueller-Felber, E.H. Niks, K. Ogata, C. Palermo, M. Pane, I. Pascual, Y. Pereon, S. Raskin, M. Rasmussen, U. Reed, U. Schara, K. Selby, C. Sobreira, Y. Takeshima, J.J. Vilchez Padilla, G. Vita, P. Vondracek, G. Wiegand, E. Wilichowski, and Schara, Ulrike (Beitragende*r)
- Subjects
0301 basic medicine ,Duchenne muscular dystrophy ,Male ,medicine.medical_specialty ,Adolescent ,Population ,six-minute walking distance ,Medizin ,Oligonucleotides ,Phases of clinical research ,Socio-culturale ,Motor Activity ,Placebo ,Pediatrics ,Dystrophin ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Statistical significance ,Medicine ,Humans ,Antisense oligonucleotide ,education ,Adverse effect ,Child ,Drisapersen ,Genetics (clinical) ,education.field_of_study ,business.industry ,Perinatology and Child Health ,medicine.disease ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,Treatment Outcome ,Neurology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Ambulatory ,Neurology (clinical) ,6-minute walking distance ,antisense oligonucleotide ,drisapersen ,dystrophin ,exon skipping ,business ,030217 neurology & neurosurgery ,Exon skipping ,Biomarkers ,Six-minute walking distance - Abstract
This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged >=5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.
- Published
- 2017
26. Additional file 3: Table S2. of Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa
- Author
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D. Hughes, R. Giugliani, N. Guffon, S. Jones, K. Mengel, R. Parini, R. Matousek, S. Hawley, and A. Quartel
- Subjects
nervous system ,mental disorders ,polycyclic compounds ,sense organs ,human activities - Abstract
Descriptive statistics on change from baseline to year 2 (MOR-001) or week 120 (MOR-005) by dosing cohort. (PDF 89 kb)
- Published
- 2017
- Full Text
- View/download PDF
27. Additional file 2: Table S1. of Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa
- Author
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D. Hughes, R. Giugliani, N. Guffon, S. Jones, K. Mengel, R. Parini, R. Matousek, S. Hawley, and A. Quartel
- Abstract
Descriptive statistics on change from baseline to year 2 (MorCAP) or week 120 (MOR-005). (PDF 74 kb)
- Published
- 2017
- Full Text
- View/download PDF
28. Additional file 5: Table S4. of Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa
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D. Hughes, R. Giugliani, N. Guffon, S. Jones, K. Mengel, R. Parini, R. Matousek, S. Hawley, and A. Quartel
- Abstract
Summary of adverse events. (PDF 64 kb)
- Published
- 2017
- Full Text
- View/download PDF
29. Additional file 1: Figure S1. of Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa
- Author
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D. Hughes, R. Giugliani, N. Guffon, S. Jones, K. Mengel, R. Parini, R. Matousek, S. Hawley, and A. Quartel
- Abstract
Study design. After completion of MOR-004, patients initially randomized to 2.0 mg/kg/week (QW-QW cohort) or 2.0 mg/kg every other week (QOW-QOW cohort) remained on their assigned dosing regimen. Patients taking placebo were randomized to one of the two dosing regimens (PBO-QOW or PBO-QW cohort, respectively). After a review of efficacy and safety results from MOR-004 established the recommended dose for part 2, all patients were switched to 2.0 mg/kg QW. Specific week of transition ranged from week 36â 96, depending on enrollment timing. (PDF 866 kb)
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- 2017
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30. Additional file 4: Table S3. of Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa
- Author
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D. Hughes, R. Giugliani, N. Guffon, S. Jones, K. Mengel, R. Parini, R. Matousek, S. Hawley, and A. Quartel
- Abstract
LS mean change from baseline to year 2 (MorCAP) or week 120 (MOR-005) based on a repeated-measures ANCOVA modela. (PDF 84 kb)
- Published
- 2017
- Full Text
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31. In vitro effect of genistein on DNA damage in leukocytes from mucopolysaccharidosis IVA patients
- Author
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Maira Graeff Burin, Luciana Giugliani, R. Giugliani, Giovana Brondani Biancini, Marion Deon, Gabriela Göethel, Graziela de Oliveira Schmitt Ribas, Giovanna Negretto, Solange Cristina Garcia, C. R. Vargas, and Rafael Fracasso
- Subjects
Adult ,Male ,Adolescent ,DNA damage ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,Genistein ,DNA Fragmentation ,Biology ,medicine.disease_cause ,Biochemistry ,Glycosaminoglycan ,chemistry.chemical_compound ,Endocrinology ,Genetics ,medicine ,Humans ,Child ,Molecular Biology ,DNA injury ,Cells, Cultured ,Dose-Response Relationship, Drug ,Mucopolysaccharidosis IV ,medicine.disease ,Molecular biology ,In vitro ,Comet assay ,chemistry ,Leukocytes, Mononuclear ,Female ,Comet Assay ,Genotoxicity - Abstract
Mucopolysaccharidosis IVA is a lysosomal storage disorder leading to an increase in glycosaminoglycans storage. Genistein is an isoflavone capable to inhibit glycosaminoglycans production. The objective of this study was to analyze the in vitro effect of different concentrations of genistein on DNA injury in mucopolysaccharidosis IVA patients. The lower concentration tested (10 μM) showed a significant increase on DNA injury in vitro, although higher concentrations (30 μM and 50 μM) showed higher DNA damage.
- Published
- 2014
32. Extended use of dried-leukocytes impregnated in filter paper samples for detection of Pompe, Gaucher, and Morquio A diseases
- Author
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R. Giugliani, Maira Graeff Burin, M. Camelier, Gabriel Civallero, and J. De Mari
- Subjects
Paper ,Pathology ,medicine.medical_specialty ,Clinical Biochemistry ,Disease ,Biochemistry ,Heparan sulfamidase ,Leukocytes ,medicine ,Humans ,Desiccation ,Enzyme Assays ,Reagent Strips ,chemistry.chemical_classification ,Gaucher Disease ,Filter paper ,biology ,Glycogen Storage Disease Type II ,Chemistry ,Galactocerebrosidase ,beta-Glucosidase ,Biochemistry (medical) ,Organ dysfunction ,Mucopolysaccharidosis IV ,alpha-Glucosidases ,General Medicine ,Chondroitinsulfatases ,Enzyme assay ,Enzyme ,Case-Control Studies ,Immunology ,biology.protein ,medicine.symptom ,Skeletal abnormalities - Abstract
Background Lysosomal storage diseases (LSD) are a group of genetic conditions which could present a vast spectrum of abnormalities that may include skeletal abnormalities, organ dysfunction, neuronal involvement, and tissue accumulation of complex molecules, among other manifestations. Definitive diagnosis of LSD is generally obtained by specific enzyme assays performed in leukocytes, fibroblasts, or more recently, dried-blood filter paper (DBFP) samples. Methods We recently introduced dried-leukocytes filter paper (DLFP) as an alternative source of enzyme to assay heparan sulfamidase and galactocerebrosidase activities, which could not be measured in DBFP samples using fluorometric methods. We present a new fluorometric methods on DLFP samples, for evaluation of α-glucosidase (GAA), β-glucosidase (GBA), and N-acetylgalactosamine-6-sulfatase (GALNS) activities, key enzyme assays for the identification of patients with Pompe disease (PD), Gaucher disease (GD), and Morquio A disease (MD), respectively. Results We show a clear discrimination between confirmed PD, GD, and MD patients and healthy controls. Conclusions We conclude that the assays of GAA, GBA, and GALNS on DLFP are reliable and useful methods for the identification of PD, GD, and MD diseases, respectively. As sample preparation is feasible in standard biochemical laboratories and transportation is very simple, it could enable patients living in remote areas to be investigated, diagnosed and eventually treated with the specific therapies available for these diseases.
- Published
- 2015
33. Selective screening of Niemann-Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis
- Author
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Kristiane Michelin, Maira Graeff Burin, Heryk Motta de Souza, Maria Luiza Saraiva-Pereira, R. Kessler, Graziela de Oliveira Schmitt Ribas, J. De Mari, Marion Deon, Carmen Regla Vargas, Caroline Paula Mescka, R. Giugliani, and Franciele Barbosa Trapp
- Subjects
0301 basic medicine ,medicine.medical_specialty ,1-Deoxynojirimycin ,Oxysterol ,Clinical Biochemistry ,Vesicular Transport Proteins ,Biology ,Biochemistry ,Filipin ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Niemann-Pick C1 Protein ,Internal medicine ,Miglustat ,medicine ,Humans ,Glycoproteins ,Niemann–Pick disease, type C ,Membrane Glycoproteins ,medicine.diagnostic_test ,Staining and Labeling ,Biochemistry (medical) ,Intracellular Signaling Peptides and Proteins ,Niemann-Pick Disease, Type C ,General Medicine ,medicine.disease ,030104 developmental biology ,Endocrinology ,Hexosaminidases ,chemistry ,Skin biopsy ,Triol ,Acid sphingomyelinase ,NPC1 ,Carrier Proteins ,030217 neurology & neurosurgery ,Brazil ,Cholestanols ,medicine.drug - Abstract
Background Niemann–Pick type C (NPC) is a treatable genetic disorder, mainly characterized by neurological dysfunction and liver damage. Its diagnosis is based on an invasive test which requires a skin biopsy to demonstrate the cholesterol accumulation in culture fibroblasts of affected patients. In the last years, new biomarkers have been investigated aiming to facilitate the diagnosis and screening of NPC; two of these possible candidates are the oxysterol cholestane-3β,5α,6β-triol (triol), a product of non-enzymatic oxidation of cholesterol, and the enzyme chitotriosidase (CT), a fully active chitinase (EC-3.2.1.14) synthesized by activated macrophages. Methods In this work, we investigated the potential use of the combined analysis of triol levels and CT activity for diagnosis, screening and monitoring of NPC in Brazilian patients, correlating with the results of Filipin staining and genetic analysis. We studied 122 untreated individuals with clinical suspicion of NPC who were separated in two groups according their concentrations of triol (higher or lower than the cutoff value of 100 ng/mL). We also analyzed blood samples from 5 patients with previous diagnosis of NPC who were under treatment with miglustat. Results The results of this work demonstrated that patients with higher concentrations of triol (group A) also presented a high activity of CT and most of them had also a positive Filipin test. Two patients of this group presented an inconclusive Filipin test, being one eventually diagnosed as NPC by molecular investigation and the other eventually diagnosed as Niemann–Pick type A or B (NPA/B) by the low acid sphingomyelinase activity presented. Three patients with high triol concentrations who had a negative result in the Filipin test presented low activities of acid sphingomyelinase, being diagnosed as NPA/B. On the other hand, triol concentrations were normal in NPC patients treated with miglustat, although CT activity in these individuals remained abnormal. In the patients with triol lower than 100 ng/mL (group B), most presented a normal activity of CT. No patient of this group had a positive Filipin test and the few patients with inconclusive Filipin test did not present pathogenic mutations in the NPC1 or NPC2 genes. Conclusions In conclusion, our data demonstrated that the combined analysis of triol and CT is quite sensitive and specific for the identification of NPC patients. Although the number of analysis in NPC patients treated with miglustat was small, the data indicate that the measurement of triol could also be potentially useful for treatment monitoring.
- Published
- 2016
34. Angiokeratoma: a cutaneous marker of Fabry’s disease
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C A Kim, C. Rivitti, D. R. Bertola, R. S. Honjo, R. Giugliani, Lilian Maria José Albano, and S. V. Kelmann
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Vascular disease ,Hyperkeratosis ,Dermatology ,Disease ,medicine.disease ,Fabry's disease ,Fabry disease ,Dyskeratosis ,Angiokeratoma ,Angioma ,medicine ,business - Abstract
The initial symptoms of Fabry's disease (FD) may seem harmless and may delay its diagnosis. A survey and screening for FD were performed on men with biopsy-proven angiokeratoma and some of their relatives (n = 29). Three patients were identified. Dermatologists should be aware of this prominent early feature and investigate unexplained cutaneous vascular lesions to detect FD.
- Published
- 2009
35. Galactosaemia in a Brazilian population: High incidence and cost–benefit analysis
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L. Oliveira de Souza, Maria Inez Machado Fernandes, C. A. Scrideli, L. M. Zanini Maciel, S. Moysés Jorge, P. Carvalho Leite, C. Souza Passador, Alceu Salles Camargo, D. Ruffato Resende, JoséSimon Camelo, R. Giugliani, and J. L. Ferreira Santos
- Subjects
Galactosemias ,Male ,Pediatrics ,medicine.medical_specialty ,UDPglucose-Hexose-1-Phosphate Uridylyltransferase ,Cost-Benefit Analysis ,DNA Mutational Analysis ,Screening programme ,Neonatal Screening ,Genetics ,False positive paradox ,Humans ,Economic analysis ,Medicine ,Genetics (clinical) ,Cost–benefit analysis ,business.industry ,Incidence ,Incidence (epidemiology) ,Infant, Newborn ,Galactose ,Confidence interval ,Colorimetry ,Female ,Brazilian population ,High incidence ,business ,Blood Chemical Analysis ,Brazil - Abstract
To study the incidence of galactosaemia in the state of Sao Paulo and the benefit/cost (B/C) ratio of the introduction of neonatal screening for galactosaemia, comparing it with a selective approach. An enzymatic-colorimetric assay was used for the screening of total galactose (TG) in a sample of 10% of the births in Sao Paulo in one year and positive cases were confirmed by the activity of galactose-1-phosphate uridyltransferase (GALT). Detected and referred cases were genotyped using enzyme restriction studies for Q188R, N314D and S135L mutations of the GALT gene. The economic analysis was determined by calculating the B/C ratio and by analysis of sensitivity as a function of the incidence of the disease detected and the variation of the interest rate in the economy. 59 953 newborns were screened for TG, with 3 cases of galactosaemia being identified (0.26% false positives), corresponding to a frequency of 1:19 984 liveborns (95% confidence interval: 1:7494 to 1:59 953). One classical case and one Duarte 2 variant referred to as a selective approach were confirmed. With an incidence of 1:19 984, the B/C ratio was 1.04 for the 11.75% interest rate in effect in Brazil, with values already decapitalized. With a maximum possible incidence of 1:7494, the B/C ratio was 2.79. There is an economic advantage in introducing neonatal screening for galactosaemia in the national neonatal screening programme. This advantage could increase with a reduction of the current interest rates in the economy.
- Published
- 2009
36. Correlation of MR Imaging and MR Spectroscopy Findings with Cognitive Impairment in Mucopolysaccharidosis II
- Author
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A. Schuch, Ana Cristina Puga, Leonardo Modesti Vedolin, A.P. Pires, R. Giugliani, Louise Lapagesse de Camargo Pinto, Ida Vanessa Doederlein Schwartz, and M. Komlos
- Subjects
Adult ,Male ,In vivo magnetic resonance spectroscopy ,Magnetic Resonance Spectroscopy ,Adolescent ,Mucopolysaccharidosis ,Statistics as Topic ,Creatine ,Pediatrics ,Group B ,White matter ,chemistry.chemical_compound ,Atrophy ,Cortex (anatomy) ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Child ,Mucopolysaccharidosis II ,Brain Chemistry ,business.industry ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Hydrocephalus ,medicine.anatomical_structure ,chemistry ,Child, Preschool ,Neurology (clinical) ,Cognition Disorders ,business ,Nuclear medicine - Abstract
BACKGROUND AND PURPOSE: There are no reliable markers to predict neurologic outcome of patients with mucopolysaccharidosis (MPS) II. We hypothesized that brain MR imaging and MR spectroscopy are useful in depicting features related to cognitive impairment (CI) in MPS II. MATERIALS AND METHODS: Nineteen male patients with MPS II were included in this study. They were evaluated through intelligence/developmental tests to be classified in 2 groups: patients with CI (group A) or patients without CI (group B). Brain MR imaging evaluated white matter (WM) lesions, hydrocephalus, and brain atrophy. Voxels from MR spectroscopy (point-resolved spectroscopy TE 30 ms) were positioned in the WM of the deep right frontal lobe and at the gray matter (GM) in the posterior occipital cortex across the midline. Comparison of MR imaging and MR spectroscopy findings between these 2 groups and a control group was performed. RESULTS: The mean age of the patients was 9.6 years (group A, 7.08 years old, 12 patients; group B, 14 years old, 7 patients; P = .076). Brain atrophy and hydrocephalus were more frequently found in group A patients ( P = .006 and P = .029, respectively); these patients also presented more severe WM lesions than patients from group B ( P = .022). Patients from group A also had a higher myo-inositol (mIns)/creatine (Cr) ratio in the GM ( P = .046) and in the WM ( P = .032). The choline/Cr and N- acetylaspartate/Cr ratios were similar in both groups. CONCLUSIONS: Our study showed that severe WM lesions, brain atrophy, hydrocephalus, and elevated mIns/Cr were more common in patients with MPS II and with CI.
- Published
- 2007
37. Improvement of sympathetic skin responses under enzyme replacement therapy in Fabry disease
- Author
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Jefferson Becker, Irenio Gomes, F. Pereira, Laura Bannach Jardim, R. Giugliani, Cristina Brinckmann Oliveira Netto, Ursula da Silveira Matte, Maira Graeff Burin, Daniel Bocchese Nora, and Luciane Kalakun
- Subjects
Male ,medicine.medical_specialty ,Sympathetic nervous system ,Time Factors ,Acroparaesthesia ,DNA Mutational Analysis ,Molecular Sequence Data ,Enzyme Therapy ,Neurological examination ,Internal medicine ,Genetics ,Humans ,Medicine ,Genetics (clinical) ,Skin ,Neurologic Examination ,medicine.diagnostic_test ,business.industry ,Vascular disease ,Age Factors ,food and beverages ,Enzyme replacement therapy ,medicine.disease ,Fabry disease ,Recombinant Proteins ,Surgery ,Isoenzymes ,Autonomic nervous system ,medicine.anatomical_structure ,Male patient ,Case-Control Studies ,Child, Preschool ,alpha-Galactosidase ,Mutation ,Cardiology ,Fabry Disease ,business - Abstract
Aim To report the effect of enzyme replacement therapy (ERT) in sympathetic skin responses (SSR) of patients with Fabry disease. Patients and methods Seven male patients were included in an open-label protocol using agalsidase-alfa, continued at regular intervals. Five patients completed 24 months of ERT and two of them completed 18 months. Two main measurements were performed at baseline, as well as 1 and 2 years after ERT: (1) a standard neurological examination (NE), with a detailed evaluation of the sensory perception of light touch, pinprick, cold, hot, and vibratory stimuli; (2) the SSR amplitudes. Results Although there were no significant differences between NE in this time period, all patients reported general improvement in their subjective reports of acroparaesthesia and sweating. Before starting ERT, the SSR amplitudes were either too small (3/7 patients) or absent (4/7 patients): the average (range) amplitude of 122 μV (0 through 492) was statistically smaller than that found in a control group, i.e. 1453.6 μV (619.7–2754) (p
- Published
- 2006
38. Nonviral in vivo gene transfer in the mucopolysaccharidosis I murine model
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R. Giugliani, Tiago Pires Dalberto, Ursula da Silveira Matte, Luisa Maria Gomes de Macedo Braga, Melissa Camassola, Nance Beyer Nardi, Maira Graeff Burin, and Andrés Delgado-Cañedo
- Subjects
DNA, Complementary ,Mucopolysaccharidosis I ,Mucopolysaccharidosis ,medicine.medical_treatment ,Transgene ,Genetic Vectors ,Intraperitoneal injection ,Dermatan Sulfate ,Spleen ,Biology ,Transfection ,Mice ,Transduction, Genetic ,In vivo ,Genetics ,medicine ,Animals ,Humans ,Tissue Distribution ,RNA, Messenger ,Genetics (clinical) ,Bone Marrow Transplantation ,Glycosaminoglycans ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Genetic transfer ,Gene Transfer Techniques ,Genetic Therapy ,Enzyme replacement therapy ,medicine.disease ,Molecular biology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Immunology ,Heparitin Sulfate ,Lysosomes ,Plasmids - Abstract
Mucopolysaccharidosis I (MPS I) is a lysosomal disorder characterized by a deficiency of the enzyme alpha-L: -iduronidase (IDUA), which is responsible for the degradation of glycosaminoglycans (GAGs). This deficiency leads to the accumulation of dermatan and heparan sulphate in lysosomes. Presently available treatments include bone marrow transplantation and enzyme replacement therapies, both of which are limited in their effects. In this work, knockout (KO) MPS I mice were treated with a nonviral vector containing the human IDUA cDNA. KO mice were transfected by hydrodynamic injection of pRIDUA in the caudal vein (i.v., n = 3) or by intraperitoneal injection of pRIDUA/Superfect complexes (i.p., n = 3). GAG concentration and IDUA activity were analysed in the kidneys, spleen, lungs, brain and liver. The expression of IDUA in the organs of i.v.- and i.p.-treated mice was also analysed by real-time reverse-transcription (RT) PCR and compared by relative quantification. The concentration of GAGs in the organs differed between KO and wild-type mice. In the spleen and liver, GAG levels were lower in i.v.- and i.p.-treated KO mice than in control nontreated animals. Real-time RT-PCR showed that the transgene is expressed in all the analysed organs of i.p.- and i.v.-treated KO mice. Enzyme activity was similarly observed in all the organs analysed. Our data suggest that this kind of transfection may be a useful tool for studies of nonviral protocols for gene therapy of MPS.
- Published
- 2005
39. Mucopolysaccharidosis VII: clinical, biochemical and molecular investigation of a Brazilian family
- Author
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R. Giugliani, Luiz Roberto da Silva, Sandra Leistner, W. S. Sly, L. A. Todeschini, Maira Graeff Burin, Ida Vanessa Doederlein Schwartz, R. M. Islam, G. N. Shah, and João Monteiro de Pina-Neto
- Subjects
Genetics ,Mucopolysaccharidosis VII ,Biology ,Genetics (clinical) - Published
- 2003
40. Effet du migalastat sur une cohorte d’hommes atteints d’une forme classique de la maladie de Fabry issue de l’étude de phase III, FACETS
- Author
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D. Germain, Nina Skuban, H. Amartino, Jay A. Barth, Jeffrey P. Castelli, R. Giugliani, William R. Wilcox, Raphael Schiffmann, Daniel G. Bichet, D. Hugues, and Christopher Viereck
- Subjects
Nephrology - Abstract
Introduction Le migalastat est un chaperon pharmacologique par voie orale qui se fixe sur certaines formes mutantes et instables de l’α GAL A, sensibles au migalastat afin de restaurer leur transfert vers le lysosome et leur activite enzymatique. Patients et methodes Des analyses en sous-groupe ont evalue le benefice du migalastat sur 24 mois, dans une cohorte de patients de sexe masculin, naifs de traitement par enzymotherapie substitutive issus de l’etude de phase III FACETS. Soixante-sept patients avec mutations sensibles ou non au migalastat ont ete randomises ; quatorze hommes sur les 50 patients randomises avec mutations sensibles presentaient une forme classique de la maladie, avec atteinte multiorganique et une activite enzymatique residuelle plasmatique de l’ α-Gal A Resultats Le DFGe CKD-EPI a l’inclusion etait de 87,8 mL/min/1,73 m 2 ( ± 33,6 DS), avec une variation annuelle moyenne a 24 mois de −0,3 (IC 95 % : −2,8, 2,3). L’IMVG a l’inclusion etait de 114 ± 27,3 g/m 2 , avec 7/14 patients presentant une HVG a baseline . L’IMVG a 24 mois etait a −16,7 g/m 2 (IC 95 % : −31,1, −2,4). Le taux plasmatique de lyso-Gb3 etait de 99,8 ± 35,3 nmol/L, avec une variation par rapport a l’inclusion a 12 mois de −36,8 (IC 95 % : −69,9, −3,7). L’echelle GSRS presentait un score a l’inclusion de 2,5 ± 1,66 avec une variation par rapport a l’inclusion a 24 mois de −0,9 (IC 95 % : − 2,1, 0,4). Discussion Le migalastat ayant demontre une efficacite chez tous les types de patients, les hommes atteints de la forme classique, les hommes atteints de la forme non classique et les femmes, ce traitement pourrait apporter un benefice a tous les patients presentant des mutations sensibles. Conclusion Ces resultats demontrent le benefice clinique du migalastat chez les hommes atteints d’une forme classique de la maladie de Fabry associee a des mutations sensibles a la fois sur la fonction renale, l’IMVG, le taux plasmatique de lyso-Gb3 et les symptomes digestifs et sont consistants avec ceux observes dans la population globale de l’etude.
- Published
- 2017
41. p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients
- Author
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G, Pasqualim, M G, Ribeiro, G G G, da Fonseca, M, Szlago, A, Schenone, A, Lemes, M V M, Rojas, U, Matte, and R, Giugliani
- Subjects
Male ,Iduronidase ,Mucopolysaccharidosis I ,Mutation ,Humans ,Enzyme Replacement Therapy ,Genetic Association Studies - Abstract
Mucopolysaccharidosis type I is a rare autosomal recessive disorder caused by deficiency of α-l-iduronidase (IDUA) which leads to a wide spectrum of clinical severity. Here, we describe the case of four male patients who present the previously undescribed p.L18P mutation. Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, claw hands and underwent bilateral carpal tunnel surgery at 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented claw hands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptide to 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease, or cognitive impairment.
- Published
- 2014
42. Glycosaminoglycans can be associated with oxidative damage in mucopolysaccharidosis II patients submitted to enzyme replacement therapy
- Author
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Marion Deon, R. Giugliani, Giovanna Negretto, Giovana Brondani Biancini, M. G. Burin, and C. R. Vargas
- Subjects
Mucopolysaccharidosis II ,business.industry ,Health, Toxicology and Mutagenesis ,Pharmacology toxicology ,Infant ,Cell Biology ,Enzyme replacement therapy ,Iduronate Sulfatase ,Pharmacology ,Toxicology ,Glycosaminoglycan ,Oxidative damage ,Oxidative Stress ,Case-Control Studies ,Child, Preschool ,Medicine ,Humans ,Enzyme Replacement Therapy ,business ,Child ,Biomarkers ,Glycosaminoglycans - Published
- 2014
43. Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients
- Author
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M. I. De Michelena, Isabella Lopes Monlleó, G. T. N. Besley, R. Giugliani, M.C.V. Garreton, Andréa de Rezende Duarte, Karen Tylee, Ana Carolina Brusius-Facchin, M. Ascurra, Angelina Xavier Acosta, Agnes Cristina Fett-Conte, Sandra Leistner-Segal, Christoph T. Zimmer, Ida Vanessa Doederlein Schwartz, R. P. Oliveira Sobrinho, Márcia Gonçalves Ribeiro, Marshall Italo Barros Fontes, Raquel Boy, Dafne Dain Gandelman Horovitz, and P. Mabe
- Subjects
Adult ,Genotype-phenotype correlation ,Genotyping Techniques ,Endocrinology, Diabetes and Metabolism ,Iduronate-2-sulfatase ,Iduronate Sulfatase ,Biology ,medicine.disease_cause ,Biochemistry ,Severity of Illness Index ,Mucopolysaccharidosis type II ,Exon ,Endocrinology ,Genetics ,medicine ,Humans ,Molecular Biology ,Genotyping ,Genetic Association Studies ,Mucopolysaccharidosis II ,Glycosaminoglycans ,Iduronate Sulfatase/genetics ,Mutation ,purl.org/pe-repo/ocde/ford#3.02.18 [https] ,Single-strand conformation polymorphism ,Hunter syndrome ,Sequence Analysis, DNA ,Exons ,South America ,medicine.disease ,Molecular biology ,Mucopolysaccharidosis II/diagnosis/genetics/pathology ,Female ,purl.org/pe-repo/ocde/ford#1.06.07 [https] - Abstract
In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (
- Published
- 2014
44. Extended use of a selective inhibitor of acid lipase for the diagnosis of Wolman disease and cholesteryl ester storage disease
- Author
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Maira Graeff Burin, Gabriel Civallero, R. Giugliani, C. Bittar, and J. De Mari
- Subjects
medicine.medical_specialty ,Cholesteryl ester storage disease ,Wolman disease ,Biology ,Selective inhibition ,Internal medicine ,Thiadiazoles ,Genetics ,medicine ,Leukocytes ,Humans ,Acid lipase ,Cells, Cultured ,Niemann-Pick Diseases ,Cholesterol Ester Storage Disease ,Wolman Disease ,Lysosomal Acid Lipase ,General Medicine ,Enzyme replacement therapy ,Lipase ,Fibroblasts ,Sterol Esterase ,medicine.disease ,Enzyme assay ,Endocrinology ,Liver ,Immunology ,biology.protein ,Carbamates ,Dried Blood Spot Testing ,Liver dysfunction - Abstract
Lysosomal acid lipase (LAL) deficiency produces two well defined inborn disorders, Wolman disease (WD) and cholesteryl ester storage disease (CESD). WD is a severe, early-onset condition involving massive storage of triglycerides and cholesteryl esters in the liver, with death usually occurring before one year of life. CESD is a more attenuated, later-onset disease that leads to a progressive and variable liver dysfunction. Diagnosis of LAL deficiency is mainly based on the enzyme assay of LAL activity in fibroblasts. Recently, a selective acid lipase inhibitor was used for the determination of enzyme activity in dried-blood filter paper (DBFP) samples. To extend and to validate these studies, we tested LAL activity with selective inhibition on DBFP samples, leukocytes and fibroblasts. Our results showed a clear discrimination between patients with LAL deficiency and healthy controls when using DBFP, leukocytes or fibroblasts (p
- Published
- 2013
45. Stillförderprogramme führen zu längeren Stillzeiten bei heranwachsenden Müttern
- Author
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E R Giugliani and O C Bica
- Published
- 2014
46. Mutations in the galactose‐1‐phosphate uridyltransferase gene of two families with mild galactosaemia variants
- Author
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B. Kleinlein, T. Podskarbi, B. S. Gathof, M. Sommer, R. Giugliani, and Yoon S. Shin
- Subjects
Adult ,Galactosemias ,Male ,medicine.medical_specialty ,Adolescent ,Glutamine ,Molecular Sequence Data ,Population ,Sequence Homology ,Biology ,Arginine ,Compound heterozygosity ,medicine.disease_cause ,Polymorphism (computer science) ,Internal medicine ,Genetics ,medicine ,Humans ,UTP-Hexose-1-Phosphate Uridylyltransferase ,Missense mutation ,Amino Acid Sequence ,Child ,education ,Gene ,Polymorphism, Single-Stranded Conformational ,Genetics (clinical) ,Mutation ,education.field_of_study ,Base Sequence ,Galactosemia ,DNA Restriction Enzymes ,medicine.disease ,Stop codon ,Endocrinology ,Child, Preschool ,Female ,Sequence Analysis - Abstract
Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.
- Published
- 1995
47. High proportion of mannosidosis and fucosidosis among lysosomal storage diseases in Cuba
- Author
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Alina González-Quevedo, Marisol Peña-Sánchez, C Menéndez-Sainz, Sergio González-García, and R Giugliani
- Subjects
Adult ,Fucosidosis ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Population ,Lysosomal storage disorders ,Mannosidosis ,Mucopolysaccharidosis type I ,Young Adult ,Epidemiology ,Genetics ,medicine ,Humans ,education ,Child ,Molecular Biology ,education.field_of_study ,business.industry ,Incidence ,Diagnostic test ,Cuba ,Infant ,General Medicine ,Middle Aged ,medicine.disease ,Child, Preschool ,alpha-Mannosidosis ,business - Abstract
Although lysosomal storage disorders (LSDs) are considered individually rare, as a group they present a non-negligible frequency. Few studies have been made of populational occurrence of LSDs; they have been conducted predominantly on Caucasian populations. We studied the occurrence of LSDs in Cuba. Data from individuals who had been referred to the Institute of Neurology and Neurosurgery in Havana from hospitals all over the country between January 1990 and December 2005 were analyzed. This institute was the only laboratory to provide enzyme-based diagnostic testing for 19 LSDs in Cuba during this period. Occurrence rates were calculated by dividing the number of postnatal diagnoses by the number of births during the study period. The combined occurrence of LSDs in Cuba was 5.6 per 100,000, lower than that reported in other studies conducted on Caucasian populations. The most frequent individual LSDs were: mucopolysaccharidosis type I (1.01 per 100,000) and, surprisingly, alpha-mannosidosis (0.72 per 100,000) and fucosidosis (0.62 per 100,000). These findings may be related to specific genetic characteristics and admixture of the Cuban population. This is the first comprehensive study of the occurrence of LSDs in Cuba. We conclude that the epidemiology of these diseases can vary regionally, and we stress the need for similar surveys in other Latin American countries.
- Published
- 2012
48. Report of a Large Brazilian Family With a Very Attenuated Form of Hunter Syndrome (MPS II)
- Author
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Israel Gomy, Gabriela Nunes Leal, Henrique Grinberg, Marcelo Luiz Campos Vieira, Sandra Leistner-Segal, R. Giugliani, C A Kim, Débora Romeo Bertola, A. C. Paula, and Caio Robledo D'Angioli Costa Quaio
- Subjects
Proband ,Pediatrics ,medicine.medical_specialty ,business.industry ,Macrocephaly ,Hunter syndrome ,Enzyme replacement therapy ,medicine.disease ,Short stature ,Asymptomatic ,Article ,medicine ,Missense mutation ,medicine.symptom ,Mucopolysaccharidosis type II ,business - Abstract
Hunter syndrome, or Mucopolysaccharidosis type II (MPS II), is a rare X-linked recessive disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). The phenotypic spectrum varies from severe to attenuated clinical forms. We report a large Brazilian family with 16 affected individuals exhibiting a very attenuated form of MPS II. Fourteen female carriers were also identified. Twelve affected male patients, whose ages ranged from 1 to 35 years, were examined. Molecular analysis showed a novel missense mutation (p.A77D) in the IDS gene, confirming the diagnosis. Nine of the family members presented some degree of heart damage, though only the proband became symptomatic and required heart transplantation. One 19-year-old adult and 1-year-old twin boys each had a normal echocardiogram. Short stature was found in two adults while macrocephaly was found in one; the remaining adults had anthropometric measures within normal range. All affected adults had normal cognitive development and were able to perform normal daily activities, except one who had mild learning disability. Two patients died due to natural causes beyond 70 years of age. The female carriers did not present any signs of disease. In this large family with a mild form of MPS II and variable degree of clinical manifestations, it is noteworthy that several affected individuals have remained asymptomatic even at advanced age and even without enzyme replacement therapy.
- Published
- 2011
49. Angiokeratoma: a cutaneous marker of Fabry's disease
- Author
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L M J, Albano, C, Rivitti, D R, Bertola, R S, Honjo, S V, Kelmann, R, Giugliani, and C A, Kim
- Subjects
Adult ,Male ,Young Adult ,Skin Neoplasms ,Biopsy ,Fabry Disease ,Humans ,Female ,Genetic Predisposition to Disease ,Middle Aged ,Child ,Angiokeratoma ,Pedigree - Abstract
The initial symptoms of Fabry's disease (FD) may seem harmless and may delay its diagnosis. A survey and screening for FD were performed on men with biopsy-proven angiokeratoma and some of their relatives (n = 29). Three patients were identified. Dermatologists should be aware of this prominent early feature and investigate unexplained cutaneous vascular lesions to detect FD.
- Published
- 2009
50. The effect of Mycoplasma and mycoplasma removal agent on the hydrolase activity in fibroblasts of patients with lysosomal diseases
- Author
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F T S, Souza, L S, Sostruznik, R C, Scolari, K J M, Castro, C V, Andrade, R, Giugliani, and J C, Coelho
- Subjects
Mucopolysaccharidosis VI ,N-Acetylgalactosamine-4-Sulfatase ,alpha-Glucosidases ,Fibroblasts ,Quinolones ,beta-Galactosidase ,Anti-Bacterial Agents ,Lysosomal Storage Diseases ,Hexosaminidase A ,Mycoplasma ,Humans ,Diagnostic Errors ,False Negative Reactions ,Cells, Cultured - Abstract
This study was designed to evaluate the effect of mycoplasma contamination on acid hydrolase activity and the action of the mycoplasma removal agent (MRA), in cultures of human fibroblasts from individuals with lysosomal diseases. For this purpose, we measured the activity of the b-galactosidase, arylsulphatase B (ASB), hexosaminidase A and a-glucosidase enzymes. The activity of the above mentioned enzymes in fibroblasts contaminated by mycoplasma was measured before and after the addition of the MRA. The results were then compared to the enzymatic activity in contamination-free cultures. Only the ASB enzyme showed significant alteration in activity both in the presence of mycoplasma and MRA. The remaining enzymes did not suffer significant interference by the presence of the two agents. Of the four enzymes tested, three did not suffer significant alterations by the presence of the mycoplasma nor from the MRA. However, the activity measured in the ASB enzyme increased significantly in the presence of mycoplasma and MRA and could lead to a doubtful diagnosis. Therefore, we suggest that contamination should be prevented by using aseptic techniques as well as the MRA in those fibroblast cultures that cannot be discarded.
- Published
- 2008
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